The upgraded role of HER3 and HER4 receptors in breast cancer
Introduction
The human epidermal growth factor receptor (HER) family consists of four members: ErbB-1 [epidermal growth factor (EGF) receptor (EGFR) or HER1], ErbB-2 (HER2) for which no ligand has been described thus far, ErbB-3 (HER3) and ErbB-4 (HER4). The shared general structure of HER receptors consists of an extracellular ligand-binding domain (ECD), a transmembrane region, and an intracellular domain containing the tyrosine kinase and a carboxy-terminal region. The HER3 receptor is unique in the family in that it is catalytically inactive. Despite their structural homology, HER receptors differ in their ligand specificities. Two main ligand classes have to date been identified: the splice variants of neuregulins (NRGs) that bind exclusively to HER3 and/or HER4 and different EGF-related proteins [1]. Binding of specific ligands to domains I and III is followed by conformational changes of the ECD, exposing domain II, which facilitates receptor dimerization. Additional receptor interactions in extracellular, transmembrane and kinase domains, further stabilize the dimer. Dimerization results in the activation of the kinase domain, and the induction of intracellular signalling cascades that mediate cell growth and survival. Signalling diversity depends both on the presence of specific receptors and the characteristics of individual ligands. EGFR and HER2 classically couple to Ras-Raf-MEK-mitogen-activated protein kinase (MAPK)-dependent pathway, whereas HER3 is a potent activator of phosphatidylinositol 3-kinase (PI3-K)-Akt [2], [3]. In terms of activity, the HER family is characterized by a functional interdependency among its members.
Section snippets
Search strategy and selection criteria
References for this review were identified by searches in PubMed from 1990 until December 2008, including the terms “ErbB receptors and breast cancer”, “ErbB3 and breast cancer”, “HER3 and breast cancer”, “ErbB4 and breast cancer”, “HER4 and breast cancer”, “ErbB3 and breast” and “ErbB4 and breast”. Articles were also identified through searches of the authors’ own files. Only papers published in English were reviewed.
HER3 and breast cancer
The HER3 gene is located on chromosome 12q13 and the encoded protein receptor binds to NRG-1 and NRG-2. Overexpression of HER3 receptor has been reported in 20–30% of invasive breast carcinomas [4]. HER3 signalling relies on the formation of heterodimers with other members of the HER family, since HER3 receptor has no intrinsic kinase activity. Although it is kinase defective, HER3 can be phosphorylated by other receptors such as HER2. Neither ligandless HER2 nor tyrosine kinase deficient HER3
HER4 and breast cancer
The HER4 gene is located on chromosome 2q33.3–34 and the encoded protein can be activated by both NRGs and some ligands of the EGF family (betacellulin, epiregulin, heparin-binding EGF-like ligand). HER4 expression is detectable in less than half of breast cancers. In contrast to the other HER receptors, the existing evidence suggests that HER4 is characterized by antiproliferative and pro-apoptotic activity [31], [32]. In cell line experiments, when HER2 positive cancer cells were transfected
Evaluating the HER family as a whole
As we have mentioned elsewhere [47], the majority of clinicopathological studies have focused on the expression and/or gene amplification of individual HER family members. Because of the complex interactions among the HER receptors, it is possible that the effect on cell proliferation and tumor growth depends on receptor trans-signalling and hence, the evaluation of the combined expression pattern of all family members merits further scrutiny. Limited data are available on the expression
Conclusion
Studies that have examined the HER family, either at the protein- or the mRNA level, have demonstrated a complex expression profile of HER receptors in patients with breast cancer. Beyond any doubt the HER family constitutes an attractive field for the development of targeted therapies and significant treatment advances have been made thus far. However, the failure of HER-targeted strategies in a substantial proportion of patients with HER2-overexpressing breast tumors reinforces the need to
Reviewers
Prof. David A. Cameron, Cookridge Hospital, NCRN Coordinating Centre, Hospital Lane, Leeds LS16 6QB, United Kingdom.
Dr. Françoise Révillion, Centre Oscar Lambret, Laboratoire d’Oncologie Moléculaire Humaine, 3 rue Frédéric Combemale, F-59020 Lille Cedex, France.
Conflict of interest statement
None.
Angelos K. Koutras, M.D., Ph.D., is a consultant medical oncologist in the Division of Medical Oncology of the University Hospital of Patras, Greece. He is also a senior research fellow at the Laboratory of Clinical Oncology of the University Hospital of Patras, Greece. His main clinical interests include breast, colorectal and lung cancer. His research interests focus on human epidermal growth factor receptor signalling pathways in breast cancer, as well as hormonal signalling in non-small
References (49)
- et al.
EGF receptor ligands
Exp Cell Res
(2003) - et al.
Oncogenic growth factor receptors: implications for signal transduction therapy
Semin Cancer Biol
(2004) - et al.
Breast cancer: The upgraded role of HER-3 and HER-4
Int J Biochem Cell Biol
(2007) - et al.
A new mutational AKTivation in the PI3K pathway
Cancer Cell
(2007) - et al.
The deaf and the dumb: the biology of ErbB-2 and ErbB-3
Exp Cell Res
(2003) - et al.
C-erbB-3 and c-erbB-2 protein expression in node-negative breast carcinoma. An immunocytochemical study
Eur J Cancer
(1994) - et al.
A natural ErbB4 isoform that does not activate phosphoinositide 3-kinase mediates proliferation but not survival or chemotaxis
J Biol Chem
(2000) - et al.
Tumor necrosis factor-alpha-converting enzyme is required for cleavage of erbB4/HER4
J Biol Chem
(2000) - et al.
Tyrosine kinases as targets for cancer therapy
N Engl J Med
(2005) - et al.
Identification of c-erbB-3 binding sites for phosphatidylinositol 3′-kinase and SHC using an EGF receptor/c-erbB-3 chimera
EMBO J
(1994)
ErbB3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor
Mol Cell Biol
ERBB3/HER3 and ERBB2/HER2 duet in mammary development and breast cancer
J Mammary Gland Biol Neoplasia
The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation
Proc Natl Acad Sci USA
Expression of c-erbB3 protein in primary breast carcinomas
Br J Cancer
Prognostic value of ERBB family mRNA expression in breast carcinomas
Int J Cancer
Expression of the HER1-4 family of receptor tyrosine kinases in breast cancer
J Pathol
Cytogenetic analysis of HER1/EGFR, HER2, HER3, and HER4 in 278 breast cancer patients
Breast Cancer Res
Expression of the ERBB3 gene product in breast cancer
Br J Cancer
C-erbB-3 protein expression in human breast cancer: comparison with other tumour variables and survival
Histopathology
C-erbB-3 in human breast carcinoma: expression and relation to prognosis and established prognostic indicators
Br J Cancer
Prognostic value of the type I growth factor receptors in a large series of human primary breast cancers quantified with a real-time reverse transcription-polymerase chain reaction assay
Clin Cancer Res
Correlated expression of erbB-3 with hormone receptor expression and favourable clinical outcome in invasive ductal carcinomas of the breast
Am J Clin Pathol
Evaluation of the prognostic and predictive value of HER family mRNA expression in high-risk early breast cancer
Br J Cancer
A naturally occurring secreted human ErbB3 receptor isoform inhibits heregulin-stimulated activation of ErbB2, ErbB3, and ErbB4
Cancer Res
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2022, Cancer Treatment ReviewsCitation Excerpt :HER3 is encoded by the ERBB3 gene, located on chromosome 12q13; known ligands for this receptor include NRG-1 and NRG-2 [44]. Of special note, HER3 does not possess kinase activity on its own, however it is capable of forming heterodimers with HER2 (and/or EGFR), which dramatically increases transphosphorylation and activation of downstream signaling cascades, in perhaps the most mitogenic stimulus in human breast cancer [44,45]. Moreover HER3 stands out among ErbB family members as a potent inducer of PI3K activity, due to direct binding with the PI3K p85 subunit [46].
Development of recombinant biomimetic nano-carrier for targeted gene transfer to HER3 positive breast cancer
2021, International Journal of Biological MacromoleculesCitation Excerpt :Although this strategy is smart and interesting, it may not be effective in targeting all breast cancer cells. It was reported that the HER3 -mediated signaling is a route for resistance to agents targeting HER2 [41]. Moreover, due to subsequent increases in membrane HER3 expression, the FDA approved HER2 targeted agents are not completely effective [42,43].
Potent dual EGFR/Her4 tyrosine kinase inhibitors containing novel (1,2-dithiolan-4-yl)acetamides
2020, Bioorganic and Medicinal Chemistry LettersNegative feedback regulation of ErbB4 tyrosine kinase activity by ERK-mediated non-canonical phosphorylation
2019, Biochemical and Biophysical Research CommunicationsCitation Excerpt :ErbB4 has four different isoforms classified by variants at the extracellular juxtamembrane domain (JM-a and JM-b) and the intracellular domain (CYT-1 and CYT-2) (Fig. 1A). Exons encoding JM-a and JM-b are alternatively spliced to produce variants sensitive (JM-a) or resistant (JM-b) to proteolytic cleavage [4,6,32]. Second alternative splicing in the intracellular domain (ICD) results in the insertion of a 16 amino acid CYT region (SEIGHSPPPAYTPMSG) [4,6,11].
Angelos K. Koutras, M.D., Ph.D., is a consultant medical oncologist in the Division of Medical Oncology of the University Hospital of Patras, Greece. He is also a senior research fellow at the Laboratory of Clinical Oncology of the University Hospital of Patras, Greece. His main clinical interests include breast, colorectal and lung cancer. His research interests focus on human epidermal growth factor receptor signalling pathways in breast cancer, as well as hormonal signalling in non-small cell lung cancer. Dr. Koutras is a member of the American Society of Clinical Oncology and a certified member of the European Society of Medical Oncology.